Clinical and demographic characteristics associated with nail involvement in alopecia areata: A cross‐sectional study of 197 patients

Abstract Background and Aims Alopecia areata (AA) is an immune‐mediated nonscarring alopecia. Nail changes are a common disfiguring feature of AA with an average prevalence of 30%. We aimed to evaluate the frequency of different types of nail changes and determine demographic and clinical associations. Methods This cross‐sectional study included 197 AA patients. Demographic and clinical variables including the Severity of Alopecia Tool (SALT) score, type of AA, and nail changes were evaluated. Results Among 197 AA patients with a mean age of 28.95 ± 14.45 years, 50.3% were female. Nail changes were detected in 165 patients (83.8%). The most frequent nail abnormalities were pitting (53.3%), linear line (46.7%), and distal notching (26.9%). AA patients with nail abnormalities were significantly younger than patients without nail changes (25.31 ± 14.96 vs. 32.22 ± 9.77 years; p < 0.001). Considering age groups, younger children (less than 10 years) were more likely to have nail changes than adults (97.1% vs. 76.5%; p < 0.001). The prevalence of linear line (69.6%) and distal notching (46.4%) were significantly higher in the universalis variant compared to other variants (p < 0.001). Pitting (54.5%), distal notching (43.9%), and koilonychia (12.1%) were the most common nail changes in severe forms compared to mild‐to‐moderate forms (p < 0.009). Conclusions Our study revealed that young patients with severe disease are prone to nail abnormalities. Pitting, distal notching, and linear line were the most common nail changes. Of note, koilonychia, leukonychia, and red spots lunula are more expected in more severe AA.


| INTRODUCTION
Alopecia areata (AA) is the most prevalent autoimmune disorder characterized by nonscaring patchy hair loss. 1,2AA affects 2% of the global population 3 and may occur at any age and peaks between the second and fourth decades of life with no sex predominance. 4,57][8] The predicted poor prognostic factors include the extent of involvement, ophiasis pattern of hair loss, long duration of hair loss, atopic diseases and other autoimmune diseases, a positive family history, and nail involvement. 9,10il involvement was first associated with AA in 1898 11 and has been reported in 7%-66% of AA patients.However, its prevalence is probably underestimated.Nail changes may be asymptomatic and therefore often overlooked in physical examination.But pain, functional problems, and a decrease in health and quality of life due to cosmetic disfigurement have also been documented.Nail changes occur more commonly in children and patients with severe variants of AA like alopecia universalis (AU) and alopecia totalis (AT).
AA-associated nail changes may occur at any time in the clinical course. 12The exact pathogenic mechanism of nail changes in AA is unknown, but it has been proposed that nails are affected by the same type of inflammatory cells that target hair follicles.Because the nails and hair follicles are similar in structure and growth. 13stopathological observations of nail changes confirm abnormalities in matrix keratinization.Therefore, the proximal nail matrix is predominantly involved compared to the nail bed which leads to clinical presentations like pitting, trachyonychia, onychomadesis, and nail thinning with or without koilonychia. 2ta regarding nail abnormalities in patients with AA are sparse.
We aimed to evaluate nail involvement and its association with demographic and clinical characteristics in patients with AA.Demographic data, family history, associated diseases such as other autoimmune diseases, and atopic dermatitis were recorded.To obtain better analytic data, we defined three age groups: ≤10, 11-18, and >18 years old.The clinical type of lesions was categorized as patchy AA, ophiasis pattern, AT, and AU.The mean duration of disease, treatment history, and severity of AA was obtained from the review of medical records.Disease duration was classified as ≤3, 3-9, ≥9 years.The severity of AA was determined by the scoring system of AA called the Severity of Alopecia Tool (SALT).The SALT score is a global severity score in percentage based on the extent and density of visual hair loss in four views of the scalp. 14SALT categories were described as follows: no hair or limited = 0%-20%; moderate = 21%-49%; severe and very severe = 50%-100%. 15Gender, age, AA variant, disease duration, and SALT score were compared between AA patients with and without nail changes.

| MATERIALS AND METHODS
Moreover, the association between each type of nail changes and these variables was evaluated.
Data analysis was performed using the IBM SPSS version 26 (IBM SPSS Statistics for Windows, Version 26.0., IBM Corp.).All categorical variables were reported as frequencies or percentages, and continuous variables were summarized using mean and standard deviation.The χ 2 and independent t-test were applied to analyze the categorical variables as appropriate.A p-value of <0.05 was considered statistically significant.The present study was approved by the ethics committee of the Tehran University of Medical Sciences.Verbal and written informed consents were obtained from each participant or their parents in case of underage by the interviewer before conducting the interview; it included an explanation regarding the method and the aims of the research.Participation in this study had no complications or additional costs for the patients.
In our study, 165 (83.8%) patients had at least one nail abnormality (49 patients [29.9%] had one nail change and the remaining more than one).The most frequent nail abnormalities included pitting in 105 (53.3%), linear line in 92 (46.7%), and distal notching in 53 (26.9%) cases.Beau's lines and onychorrhexis were rare findings.The complete details of nail changes are listed in Supporting Information: Table 1.

| Comparison between AA patients with and without nail findings
As shown in Table 1, AA patients with nail abnormalities were significantly younger than patients with no nail changes (p < 0.001).
Patients with nail changes had more frequently severe AA variants (AT and AU) and higher SALT scores, however, the difference was not statically significant (p < 0.18).
The prevalence of nail changes was not significantly different between men and women (p < 0.26).Nevertheless, trachyonychia Leukonychia in ophiasis (n = 1; 10%) (p < 0.02) and koilonychia (n = 4; 20%) in totalis variant (p < 0.01) were the frequent changes.Data regarding the most common nail changes is provided in Table 2. Additionally, the complete list of the aforementioned associations is illustrated in Supporting Information: Table 1.
The prevalence of nail changes was significantly associated with disease severity (p < 0.03).Pitting (n = 36; 54.5%), distal notching (n = 29; 43.9%), and koilonychia (n = 8; 12.1%) were the highest changes in severe forms compared to mild to moderate forms (p < 0.009).(Figure 2; Supporting Information: F I G U R E 2 Associations between disease severity based on Severity of Alopecia Tool (SALT) score and nail changes.
Due to the rarity of atopic dermatitis and other autoimmune diseases, we could not evaluate their relationship with nail changes.

| DISCUSSION
AA is the most prevalent autoimmune disorder characterized by nonscaring patchy hair loss.Nail involvement has been reported in 7%-66% of AA patients and it has been proposed as one of the poor prognostic factors. 12However, its prevalence is probably underestimated and overlooked in physical examination.We evaluated nail involvement and its association with demographic and clinical characteristics in patients with AA.Our patients were on average young AA patients with almost 8 years of AA history and moderate to severe disease involvement.We found positive family history of AA in 17.8% of our patients.The most common AA variant was the patchy pattern and then universalis, and tofacitinib was the most commonly prescribed drug.More than 80% of our AA patients had at least one nail abnormality; pitting, linear line, and distal notching were among the most frequent nail findings.On average AA patients with nail abnormalities were younger than patients with no nail changes and had more severe disease involvement.Moreover, some nail abnormalities were specifically associated with gender like brittle nails, trachyonychia, and linear line.
7][18] Arousse et al. 19 showed positive family history in 22.1% of AA patients and proposed thyroid disease as the most common autoimmune comorbidity (12.7%).This is in agreement with our results which detected AA family history in 17.8% and autoimmune comorbidities in 2.5% of the patients including Hashimoto thyroiditis.Our results showed that positive family history of AA is more common than autoimmune comorbidities.
In our study, almost 84% of the patients had at least one nail abnormality.Yesudian et al. 20 in a review study had shown that about 30% of AA patients (range 7%-66%) had nail involvement.A higher prevalence of nail abnormalities in our patients might be due to the large proportion of patients with high SALT scores and severe AA; the mean SALT score was almost 43%.Of note, in our study either severe AA variants (totalis and universalis) or higher SALT scores were considered as severe AA, however, the majority of the researchers who studied AA-associated nail changes did not report the severity based on the SALT scoring system.The most prevalent AA patterns were patchy (56.3%) and universalis (28.4%).This finding supports previous studies reporting patchy (49.5%) and universalis (27.5%) patterns as the most common AA variants. 19The most frequent nail abnormalities included pitting and linear lines in almost half of the patients.These results match those observed in earlier studies.2][23][24][25][26] These results support the fact that the proximal nail matrix is predominantly affected by AA than the distal matrix and nail bed involvement. 27To have a better understanding of the frequency of nail changes, we have used a table from a review study and compared the results (Table 3). 12e results of this study indicated that AA patients with nail abnormalities had more severe disease involvement than patients with no nail changes.In other words, nail changes were observed in 37.7% of the patients with a SALT score of more than 50 and in 29% of the cases with a SALT score of less than 20.[28][29][30] Garcia-Hernandez et al. 22 has proved that the risk of progression to AT and AU is 8.44 times more likely when nail changes are present.
Due to a higher proportion of nail changes in AA patients suffering from extensive disease involvement, nail changes have been suggested to be a poor prognostic factor. 12,24Furthermore, some studies have indicated that nail abnormalities act as an independent risk factor for treatment-refractory AA. 10,[31][32][33] The most important clinically relevant finding was the fact that some of the nail changes were significantly associated with disease severity.Distal notching, linear line, and koilonychia had positive associations that could be suggested as poor prognostic factors.On the other hand, yellow-brown discoloration showed no significant association.Moreover, red spots on the lunula were observed in two cases with universalis pattern that interestingly confirmed the previous reports suggesting this nail abnormality as the most specific sign of severe AA. 2,28 In our study, AA patients with nail abnormalities were younger (25.31 ± 14.96In the current study, gender was not associated with nail changes.This result does not support previous findings with some tendencies regarding gender. 2,34We have demonstrated that even though the prevalence of nail findings was not significantly different between men and women, some nail findings were more commonly observed between sexes such as brittle nails that were frequent changes in women and trachyonychia and linear line which occurred more significantly in men.Our results were in accordance with Tosti et al. 32 which found trachyonychia more frequently in men than women.
One limitation of this study is the small sample size.Second, the evaluation of treatment response regarding nail changes is limited by the use of a cross-sectional design.Therefore, the current study was not specifically designed to assess the impact of the nail abnormalities on the course of the AA and the response to treatment and also was unable to identify the best drug choice considering the associated nail change.Third, the current study did not perform dermoscopy and nail biopsy.A further study could explore nail changes more precisely using dermoscopy or assess the clinical and pathological associations using nail biopsy.

| CONCLUSION
To our knowledge, this is the first study that not only compared AA patients regarding the presence of nail changes but has also investigated several types of nail changes and their associations with demographic and clinical variables.Previous studies have generally discussed nail abnormalities in AA and assessed their effect on AA progression.Our study revealed that young patients with moderate to severe disease involvement are prone to suffer from nail abnormalities.In addition to pitting, distal notching, and linear line as the most common nail changes, koilonychia, leukonychia, and red spots on the lunula may be poor prognostic predictors for severe AA.
Onychomadesis was a rare change exclusively observed in children.
Due to the novelty of the current study, future prospective studies with larger study populations using multivariate regression analysis are strongly recommended to identify risk factors for AA-associated nail changes.Further work needs to be done to establish the poor prognostic nail changes associated with treatment response and also it would be interesting to identify the optimal therapeutic option regarding specific nail changes.

A
cross-sectional study was conducted on a sample of 197 confirmed AA patients between 2021 and 2022, referred to dermatology departments of Imam Khomeini and Razi hospitals, Tehran University of medical sciences, Tehran, Iran.The included AA patients were then evaluated by two expert dermatologists for the presence of nail findings.Nails were also carefully examined for subungal hyperchratosis and onychodytrophy, and KOH mount and culture for dermatophytes were performed when necessary to rule out onychomychosis.Nail changes were attributed to AA after exclusion of other cutaneous or systemic diseases, including psoriasis.The inclusion criteria were all the confirmed AA patients referred to dermatology departments of Imam Khomeini and Razi hospitals between 2021 and 2022 regardless of age, gender, and disease duration.The exclusion criteria were as follows: 1.Recent history of nail trauma; 2. Acute or chronic nail diseases (except AA-associated) in the past 3 months; 3. No consent to participate in research.

Table 2
). Characteristics of patients with and without nail changes.